A large and growing number of applications require porphyrinic macrocycles that are water-soluble and are suited for conjugation in a variety of formats. The applications encompass flow cytometry, cellular and whole-organism imaging, sensing, photodynamic therapy, biomimetic catalysis, and radical scavenging. The success of these applications relies on a host of factors, including (1) significant solubility in aqueous saline solutions, thereby avoiding intermolecular aggregation (and excited-state quenching), (2) minimal non-specific binding to cellular components, (3) incorporation of a single reactive group for conjugation, thereby avoiding crosslinking and mixtures of products, and (4) robust synthesis affording ample quantities for experimentation.
The large hydrophobic face of porphyrinic macrocycles presents a challenge to water-solubilization. Prior approaches to achieve water solubility of porphyrins have largely relied on uroporphyrin,1 meso-tetrakis[4-(N-methyl)pyridinium]porphyrin,2 and meso-tetrakis(4-sulfophenyl)porphyrin2 (Chart 1).
Other approaches have entailed attachment of the following motifs to the porphyrin via a meso-aryl group: oligoethylene glycol (OEG) attached to a phenol,3,4 multi-OEG dendrimers,5 glycosyl units attached to phenols,6 and alkyl polyamine7 or polycarboxy chains.8 While each group has merit, the porphyrins shown in Chart 1 are not suited for bioconjugation, and some of the other groups examined have mass>10-times that of porphyrin. With the exception of the very recent work of Sessler,9 few new water-solubilizing motifs have been investigated for use with porphyrinic macrocycles.
In addition to water solubility, the presence of a bioconjugatable group is essential for attachment to substances ranging from nanoparticles to biological targeting agents. Indeed, porphyrinic molecules have been attached to diverse targeting agents including peptides,10 estrogen,11 acridine,12 antibodies,13 transferrin,14 epidermal growth factor,15 low density lipoprotein,16 nucleic acids,17 and polymers such as polylysine18 or polyvinyl alcohol.15 In each of these cases, the success of the bioconjugation places a premium on high solubility of the porphyrinic compound in aqueous media.
We recently found that branched-alkyl groups (e.g., tridec-7-yl) known as ‘swallowtail’ substituents are very effective in imparting a high level of organic solubility to porphyrins.19
The long hydrocarbon chains of the swallowtail motif project over both surfaces of the plane of the macrocycle, suppressing π-π interaction between the porphyrin rings.19 Such hydrocarbon swallowtails were shown earlier to impart excellent solubility in organic media to perylene dyes, which otherwise are quite insoluble.20 By contrast, the majority of prior water-solubilization motifs for use with porphyrins have relied on meso-aryl substituents that provide little facial encumbrance (Chart 1).